Well-defined transition metal carbene complexes have emerged as the catalysts of choice for a wide variety of selective olefin metathesis transformations [F. Z. Dörwald, Metal Carbenes in Organic Synthesis; Wiley VCH, Weinheim, 1999]. These transformations include olefin cross metathesis (CM), ring-opening metathesis (ROM), ring-opening metathesis polymerization (ROMP), ring-closing metathesis (RCM), and acyclic diene metathesis (ADMET) polymerization [K. J. Ivin and J. C. Mol, Olefin Metathesis and Metathesis Polymerization; Academic Press, London, 1997]. Of particular importance has been the development of ruthenium carbene catalysts demonstrating high activity combined with unprecedented functional group tolerance [T. M. Trnka and R. H. Grubbs, Acc. Chem. Res., 2001, 34, 18–29]. Olefin metathesis serves as a key reaction for the development of a range of regioselective and stereoselective processes. These processes are important steps in the chemical synthesis of complex organic compounds and polymers and are becoming increasingly important in industrial applications. [see for example Pederson and Grubbs U.S. Pat. No. 6,215,019].
An initial concern about using ruthenium olefin metathesis catalysts in commercial applications has been reactivity and catalyst lifetime. The original breakthrough ruthenium catalysts were prinarily bisphosphine complexes of the general formula (PR3)2(X)2Ru═CHR′ wherein X represents a halogen (e.g., Cl, Br, or I), R represents an alkyl, cycloalkyl, or aryl group (e.g., butyl, cyclohexyl, or phenyl), and R′ represents an alkyl, alkenyl, or aryl group (e.g., methyl, CH═CMe2, phenyl, etc.). Examples of these types of catalysts are described in U.S. Pat. Nos. 5,312,940, 5,969,170 and 6,111,121. Though they enabled a considerable number of novel transformations to be accomplished, these bisphosphine catalysts can exhibit lower activity than desired and, under certain conditions, can have limited lifetimes.
More recent developments of metathesis catalysts bearing a bulky imidizolylidine ligand [Scholl et. al. Organic Letters 1999, 1, 953–956] such as 1,3-dimesitylimidazole-2-ylidenes (MES) and 1,3-dimesityl-4,5-dihydroimidazol-2-ylidenes (IMES), in place of one of the phosphine ligands have led to greatly increased activity and stability. For example, unlike prior bisphosphine complexes, the various imidizolyidine catalysts effect the efficient formation of trisubstituted and tetrasubstituted olefins through catalytic metathesis. Examples of these types of catalysts are described in PCT publications WO 99/51344 and WO 00/71554. Further examples of the synthesis and reactivity of some of these active ruthenium complexes are reported by A. Fürstner, L. Ackermann, B. Gabor, R. Goddard, C. W. Lehmarm, R. Mynott, F. Stelzer, and O. R. Theil, Chem. Eur. J., 2001, 7, No. 15, 3236–3253; S. B. Gaber, J. S. Kingsbury, B. L. Gray, and A. H. Hoveyda, J. Am. Chem. Soc., 2000, 122, 8168–8179; Blackwell H. E., O'Leary D. J., Chatterjee A. K., Washenfelder R. A., Bussmann D. A., Grubbs R. H. J. Am. Chem. Soc. 2000, 122, 58–71; Chatterjee, A. K., Morgan J. P., Scholl M., Grubbs R. H. J. Am. Chem. Soc. 2000, 122, 3783–3784; Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791–799; Harrity, J. P. A.; Visser, M. S.; Gleason, J. D.; Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 1488–1489; and Harrity, J. P. A.; La, D. S.; Cefalo, D. I; Visser, M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 2343–2351.
The improvements in catalyst activity and expansion of potential substrates resulted in the ruthenium metathesis systems becoming attractive candidates for use in industrial scale processes. In particular, many of the targeted products of olefin metathesis are useful as intermediates in flavors and fragrances, pharmaceuticals and other fine chemicals. Thus, a second major concern has involved ruthenium residues that may be present in the products produced by metathesis. To address this issue, several catalyst removal techniques have been developed [Maynard and Grubbs in Tetrahedron Letters 1999, 40, 4137–4140; L. A. Paquette, JD. Schloss, I. Efremov, F. Fabris, F. Gallou, J. Mendez-Andino and J. Yang in Org. Letters 2000, 2,1259–1261; and Y. M. Ahn; K. Yang, and G. I. Georg in Org. Letters 2001, 3, 1411], including that described by Pederson and Grubbs [Pederson and Grubbs, U.S. Pat. No. 6,215,049] which is still the most amenable to large scale reactions. Ruthenium metathesis catalysts with a wide range of reactivity and that could be easily removed from the product were now available.
Further progress towards catalyst selectivity, stability, and removal has been recently published by Hoveyda and others [Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791–799] with the demonstration of new, readily recyclable catalyst systems containing chelating carbene species (FIG. 1) that are exceptionally stable and can even be purified by column chromatography in air. For example, the tricyclohexylphosphine-ligated variant, Catalyst 601 (FIG. 1), can be recovered in high yield from the reaction mixture by simple filtration through silica. Hoyveda and coworkers also demonstrated [Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organometallic Chemistry 2001, 624, 327–332] that by replacement of the phosphine with the sMES ligand, Catalyst 627 (FIG. 1) actively promotes the cross-metathesis of acrylonitrile and terminal olefins in moderate to excellent yields (20% to 91%) with a cis to trans olefin ratios that range from 2:1 to over 9:1. Related chelating carbene catalysts are described in U.S. Patent Application Publication No. 2002/0107138 and U.S. Pat. No. 6,306,987.
